The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11
The Deubiquitylase OTUB1 Mediates Ferroptosis via Stabilization of SLC7A11
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DOI：
10.1158/0008-5472.can-18-3037
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发表时间：
2019-04-15
期刊：
影响因子：
11.2
通讯作者：
Gu, Wei
中科院分区：
文献类型：
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作者：
Liu, Tong;Jiang, Le;Gu, Wei
虽然细胞周期阻滞、衰老和凋亡是肿瘤抑制的既定机制，但越来越多的证据表明，铁依赖性、非凋亡形式的细胞死亡是抑制肿瘤发展的一种新的调控途径。铁凋亡是由脂质过氧化引发的，并受到胱氨酸-谷氨酸反向转运蛋白的关键组分SLC 7A 11的严格调节。尽管许多研究证明了SLC 7A 11的转录调控在铁中毒反应中的重要性，但在人类癌症中如何控制SLC 7A 11的稳定性在很大程度上仍然未知。在这项研究中，我们利用生化纯化，以确定泛素水解酶OTUB 1作为一个关键因素，在调节SLC 7A 11的稳定性。OTUB 1直接与SLC 7A 11相互作用并使其稳定;相反，OTUB 1敲低降低了癌细胞中的SLC 7A 11水平。OTUB 1在人类癌症中过表达，OTUB 1的失活使SLC 7A 11不稳定，并导致小鼠中肿瘤异种移植物的生长抑制，这与铁凋亡的活化减少有关。值得注意的是，癌症干细胞标志物CD 44的过表达通过促进SLC 7A 11和OTUB 1之间的相互作用增强了SLC 7A 11的稳定性; CD 44的缺失部分消除了这种相互作用。CD 44表达以OTUB 1依赖性方式抑制癌细胞中的铁凋亡。总之，这些结果表明OTUB 1在控制SLC 7A 11的稳定性和CD 44介导的对人类癌症中的铁凋亡的作用中起着至关重要的作用。
Although cell-cycle arrest, senescence, and apoptosis are established mechanisms of tumor suppression, accumulating evidence reveals that ferroptosis, an iron-dependent, nonapoptotic form of cell death, represents a new regulatory pathway in suppressing tumor development. Ferroptosis is triggered by lipid peroxidation and is tightly regulated by SLC7A11, a key component of the cystine-glutamate antiporter. Although many studies demonstrate the importance of transcriptional regulation of SLC7A11 in ferroptotic responses, it remains largely unknown how the stability of SLC7A11 is controlled in human cancers. In this study, we utilized biochemial purification to identify the ubiquitin hydrolase OTUB1 as a key factor in modulating SLC7A11 stability. OTUB1 directly interacted with and stabilized SLC7A11; conversely, OTUB1 knockdown diminished SLC7A11 levels in cancer cells. OTUB1 was overexpressed in human cancers, and inactivation of OTUB1 destabilized SLC7A11 and led to growth suppression of tumor xenografts in mice, which was associated with reduced activation of ferroptosis. Notably, overexpression of the cancer stem cell marker CD44 enhanced the stability of SLC7A11 by promoting the interaction between SLC7A11 and OTUB1; depletion of CD44 partially abrogated this interaction. CD44 expression suppressed ferroptosis in cancer cells in an OTUB1-dependent manner. Together, these results show that OTUB1 plays an essential role in controlling the stability of SLC7A11 and the CD44-mediated effects on ferroptosis in human cancers.